This work will establish the role, and precise mechanism, involved in renal regulation of nitrogen partitioning between urea, and end product, and glutamine, an important intermediate in many biosynthetic processes. As a consequence of this process, nitrogenous precursors, ammonia and alpha-amino nitrogen, are shunted from loss of urea to the intermediate glutamine. This novel regulatory role is of particular importance in metabolic acidosis. Since, in this condition, excess acid necessitates renal ammonia (base) production for excretion of the acid as ammonium ions, the kidney must have an available supply of potential ammonia. In rat, dog and man, this occurs as the amide and amino nitrogens of glutamine. Consequently the kidneys not only produce base (NH3) for acid excretion as part of the adaptation to acidosis but signal extrarenal glutamine production ensuring supply keeps pace with renal demand. This regulatory mechanism is all the more critical since renal glutamine uptake appears to be a passive process making ammonia production highly dependent upon extrarenal glutamine formation. The nitrogen incorporated into glutamine during chronic acidosis comes at the expense of urea precursors; this perhaps explains the observation that protein deficient humans do not adequately respond to acidosis. Clearly then a second important finding will be the renal regulation of urea formation in acidotic animals. If the signal by which the kidney turns off urea, and on glutamine formation, is in fact increased renal vein ammonia content, then inhibitor (high concentration) of urea formation presents itself. The concept of organ system feedback (kidney acting on liver and possibly muscle) at the molecular level is an important step toward integrating physiological and biochemical systems. The importance of such a unified concept is clear when considering problems involving uremic patients.